The human immunodeficiency viruses, type 1 and 2 (HIV-1 and HIV-2), appear to have originated by cross-species transmission of simian immunodeficiency virus (SIV) from asymptomatically infected African primates. Of the viruses characterized to date, only those originating from sooty mangabeys (SIVsm) efficiently infect human primary lymphocytes, consistent with the appearance of the genetically-related HIV-2 in humans. Further study of the lentiviruses infecting nonhuman primates is important because it may provide insight into the origins and evolution of HIV in humans. In this study, we characterized a novel SIV isolate from an East African monkey of the Cercopithecus genus, l=hoest monkey (C. l=hoesti), which we designated SIVlhoest. This SIV isolate efficiently infected both human and macaque lymphocytes and resulted in persistent infection of macaques characterized by high primary virus load and a progressive decline in circulating CD4 lymphocytes consistent with progression to AIDS. Phylogenetic analyses showed that SIVlhoest is genetically distinct from other previously characterized primate lentiviruses but clusters in the same lineage as SIV from mandrills (SIVmnd), a West African primate species. The phylogenetic relationship between these SIV isolates suggests that SIVmnd origi nated by cross-species transmission from a West African relative of the l=hoest monkey. This observation lends support to the hypothesis that the primate lentiviruses originated and co-evolved within monkeys of the Cercopithecus genus. Regarded in this light, documentation of SIV in other primates such as mandrills, baboons, mangabeys and humans, may actually be the result of relatively recent cross-species transmission. FUNDING NIAID Intramural Program PUBLICATIONS None